Metabolic syndromes represent risk factors such as hypertriglyceridemia, hypertension, abnormal glucose metabolism, abnormal blood coagulation, and obesity and may cause diseases such as heart attack, ischemic heart diseases, type 2 diabetes, hypercholesterolemia, cancers, gallstones, arthritis, arthralgia, respiratory diseases, sleep apnea, benign prostatic hyperplasia, menstrual irregularity, and the like. Therefore, metabolic syndromes pose a great threat to modem people. According to a National Cholesterol Education Program (NCEP) standard published in America, 2001, a patient is judged to have a metabolic syndrome when the patient presents with at least one of {circle around (1)} a waist size of 40 inches (102 cm) or more in men, a waist size of 35 inches (88 cm) or more in women, {circle around (2)} triglycerides of 150 mg/dL or more, {circle around (3)} HDL cholesterol of 40 mg/dL or less in men and 50 mg/dL or less in women, {circle around (4)} a blood pressure of 130/85 mmHg or more, {circle around (5)} fasting glucose of 110 mg/dL. In Asians, when men have a waist size of 90 cm or more and women have a waist size of 80 cm or more, they are judged to have abdominal obesity. When such standards were applied to Koreans, it was recently reported that approximately 25% Koreans have metabolic syndromes.
Chronic and long-term high-calorie intake is considered as a major risk factor of such metabolic syndromes. Metabolic efficiency is reduced due to excessive energy intake, lack of exercise, life extension, aging, and the like, thereby causing obesity, diabetes, and metabolic syndromes due to excessive caloric intake.
As treatment methods, diet therapies, exercise therapies, behavioral control therapies, drug treatments, and the like are carried out. However, since exact causes of metabolic syndromes are not known, treatment effects are presently insignificant and symptoms are merely alleviated or progression of diseases is delayed. A variety of therapeutic targets have been identified but an excellent treatment target has yet to be reported.
Meanwhile, since NADH and NADPH are used in a fat biosynthesis process when ratios of NAD+/NADH and NADP+/NADPH are reduced and, thus, NADH and NADPH remain in vivo or in vitro, and NADH and NADPH are used as major substrates causing reactive oxygen species (ROS) when present in excess, ROS causes diseases such as inflammatory diseases. For these reasons, if in vivo or in vitro environment may be changed such that a state, in which ratios of NAD+/NADH and NADP+/NADPH are increased, is stably maintained, fat oxidation due to NAD+ and NADP+ and a variety of energy consumption metabolism may be activated. As a result, if an action mechanism to continuously keep the low concentration of NAD(P)H can be activated, a variety of diseases including obesity may be treated by inducing consumption of excessive calories.
To increase the concentration and a ratio of NAD(P)+ which is a signal messenger known as performing a variety of functions as described above, methods below are considered: first, a method of controlling a salvage synthesis process as an NAD(P)+ biosynthesis process; second, a method of increasing the concentration of NAD(P)+ in vivo by activating genes or proteins of enzymes using NAD(P)H as a substrate or a coenzyme; third, a method of increasing the concentration of NAD(P)+ by supplying NAD(P)+ or an analogue, derivative, precursor, or prodrug thereof from the outside; and the like.
NAD(P)H:quinone oxidoreductase (EC1.6.99.2) is called DT-diaphorase, quinone reductase, menadione reductase, vitamin K reductase, azo-dye reductase, or the like. Such NQO exists in two isoforms, namely, NQO1 and NQO2 (ROM. J. INTERN. MED. 2000-2001, vol. 38-39, 33-50). NQO is a flavoprotein and facilitates removal of quinone or quinone derivatives through detoxification reaction. NQO uses NADH and NADPH as electron donors. Activation of NQO prevents formation of highly reactive quinone metabolites removes benzo (d)pyrene or quinone, and lowers toxicity of chrome. Although activation of NQO occurs in all tissues, activation thereof depends on tissue types. Generally, it was confirmed that expression of NQO was increased in cancer cells and tissues such as the liver, stomach, kidney, and the like. Expression of the NQO gene is induced by xenobiotics, antioxidants, oxidants, heavy metals, ultraviolet light, radiation, and the like. NQO is a part of lots of cellular defense mechanisms induced by oxidative stress. Combined expression of genes related to defense mechanisms including NQO protects cells against oxidative stress, free radicals, and neoplasia. NQO has very broad substrate specificity and, as substrates thereof, quinone, quinone-imines, and nitro and azo compounds may be used.
Thereamong, NQO1 is mainly expressed in epithelial cells and endothelial cells. This means that NQO1 may function as a defense mechanism against compounds absorbed through air, the throat, or blood vessels. Recently, it was reported that expression of an NQO1 gene greatly increased in adipose tissues of humans having metabolic syndrome and expression of NQO1 in larger adipose cells was statistically significantly high. When weight loss was induced through diet treatments, expression of NQO1 proportionally decreased with weight loss. It was confirmed that the amount of NQO1 mRNA is proportional to GOT and GPT known as indicators of fatty liver syndrome. Therefore, it is judged that NQO1 may play a role in metabolic syndromes related to obesity, when it is considered that expression of NQO1 in adipose tissues relates to adiposity, glucose tolerance, and liver function index (Journal of Clinical Endocrinology & Metabolism 92 (6):2346. 2352).